Ion Exchange Resin Treated to Control Swelling

ABSTRACT

The present invention provides a method and composition are provided for loading one or more drugs in a solution onto one or more ion exchange resin particles to form a drug-loaded resin particle. The drug-loaded resin particle is a sustained-release coated layered pharmaceutical drug-ion exchange resin having a one or more pharmaceutically active drugs applied directly to a non-equilibrated ion exchange resin to form a drug-resin complex. The drug-resin complex then coated is shelf stable.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/225,834, filed Sep. 13, 2005, the contents of which areincorporated by reference herein in its entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates generally to the controlled-release ofactive agents, and in particular, to compositions and methods enhancethe efficiency in preparing ion exchange resins and pharmacologicallyactive drugs adsorbed to ion exchange resin.

BACKGROUND OF THE INVENTION

Without limiting the scope of the invention, its background is describedin connection with ion exchange resins, as an example. Currently, ionexchange resins used in pharmaceutical applications serve a variety offunctions, e.g., providing sustained-release, masking tastes,eliminating polymorphism, improving the dissolution of poorly solubledrugs, eliminating deliquescence, reducing water uptake, improvingstability, reducing abuse liability and improving physicalcharacteristics of pharmacologically active drugs. For example, ionexchange resins are used to prolonged the continuous release ofpharmacologically active drugs by absorbing the drug to the ionicexchange resin to form a drug-resin complex in which the drug isreleased over time. In certain instances, a rate controlling coating isapplied to the drug-resin complex to prolong the release of thepharmacologically active drug.

The sustained-release drug-resin complex provides a controlled-releaseof the pharmacologically active drug over a given period of time. Thus,these complexes allow a continuous or intermittent supply of the activedrug to a subject. The sustained-release drug-resin complex provides aconvenient dosage form that provides a therapeutic drug levelsthroughout an extended period. The release of the drug maintains atherapeutically effective plasma level significantly longer than thatgiven by a typical drug dosage form.

In a general sense, an ion exchange resin can be described as anassembly of polymers that contain ionizable groups distributed along thepolymer backbone. The ionizable groups of the polymer backbone areassociated with ions. When the polymer is combined with a solution ofcounter ions, the counter ions in the solution exchange with the ions ofthe polymer and the counter ions are physically removed from thesolution. Therefore, counter ions (e.g., drug ion) in solution canexchange with the ions of the ion exchange resin (e.g., polymer) throughan ionic interaction, as opposed to a covalent interaction. Thepharmacologically active drug ions can then be eluted from the ionexchange resin to treat the subject.

A substantial portion of the active drug is ionically bound within thepolymer matrix of the ion exchange resin. The active drug elutes fromthe polymer matrix over time to provide a specific release profile. Thesize of the adsorbed drug molecule and/or the size of the polymer resinparticle (e.g., the cross linkage of the cationic exchange resin) may bealtered to control the elution rate. The process of adsorption of apharmacologically active drug to ion exchange resin is a well-knowntechnique to the skilled artisan and the subject of many United Statesand foreign patents. Generally, adsorption is accomplished by mixing apharmacologically active drug and an ion exchange resin in an aqueoussolution, filtering, washing, drying and optionally coating thedrug-resin complex with a water-permeable diffusion barrier.

For example, U.S. Pat. No. 4,996,047 discloses oral pharmaceuticalpreparations, which include a pharmacologically active drug bound to anion-exchange resin to provide a drug-resin complex having a drug contentabove a specified value. The drug-resin complex is subsequently coatedwith a water-permeable diffusion barrier coating that is insoluble ingastrointestinal fluids. Thus, the release of drug is controlled underconditions encountered in the gastrointestinal tract.

One of the major disadvantages with the use of an ion exchange resin asa pharmaceutical delivery agent is that ion exchange resin particles aresusceptible to swelling. For example, ion exchange resins drug complexescan undergo significant swelling when the dry, non-hydrated drug complexcontacts fluids, e.g., water, biological fluids, gastrointestinalfluids. The swelling of the ion exchange resin often ruptures thediffusion barrier coating, which causes a loss of control of thediffusion rate of the drug and alters the drug release profile.

U.S. Pat. No. 4,847,077 (the '077 patent) discloses sulfonic andcationic exchange resins treated with a critical amount of glycerin toenhance their coatability. The specification discloses methods toachieve prolonged continuous release of a pharmacologically activemonobasic drug absorbed on a sulfonic acid cationic exchange resintreated with a critical amount of glycerin. Specifically,controlled-release pharmaceutical preparations containing coatedsulfonic acid cationic exchange resin drug complex particles are taught,that are treated prior to coating with about 15 to 25% by weight ofglycerin.

Finally, U.S. Pat. No. 4,221,778 (the '778 patent) teaches apharmaceutical preparation containing a diffusion barrier coated ionexchange resin drug complex treated with a solvating agent. Thesolvating agent retards the rate of swelling in water but does notreduce the overall amount of swelling, only the rate at which swellingoccurs. The '778 patent claims a pharmaceutical preparation having ionexchange resin particles with a pharmacologically active drug absorbedthereon to form drug-resin complex particles. The resin particles havebeen treated with an impregnating agent (e.g., polyethylene glycol,propylene glycol, mannitol, lactose and methylcellulose) in an amountsufficient to retard the rate of swelling in water and subsequentlycoated with a water-permeable diffusion barrier.

SUMMARY OF THE INVENTION

The present inventors recognized a need for a pharmacologically activedrug-resin complex that does not swell or alter the release rate whencontacted with fluids, while reducing the concentration of swellingagent used in the formulations and increasing the compatibility of theswelling reducing agent with pharmacologically active drugs.

The foregoing problems have been recognized for many years and whilenumerous solutions have been proposed, none of them adequately addressall of the problems in a single composition, e.g., controlling theswelling, reducing the concentration of swelling agent, increasing theeffectiveness of the swelling controlling agent and increasing thecompatibility of the swelling reducing agent with pharmacologicallyactive drugs.

In addition, the present inventors recognized that the methods usedcurrently to load active compounds onto ion exchange resins (e.g., the'778 patent and the 077 patent) involve loading an active compound ontoan ion exchange resin by preparing a solution of the active compound inthe presence of the ion exchange resin and allowing the active compoundto equilibrate between the ion exchange resin and the solution. Theequilibrium results in a portion of active compound being bound to theion exchange resin and a portion of the active compound being unbound insolution. After allowing time for equilibration, the suspension isfiltered to remove excess active compound, then washed and refiltered toremove free active compound. After drying, an active compound/ionexchange resin complex is recovered; however, this multi-step procedureprovides many steps at which the product may be lost and/or theequilibriums may be shifted.

The present invention provides a sustained-release coated pharmaceuticaldrug-ion exchange resin composition. The composition includes a coatingapplied to a pharmaceutically active drug applied directly to anon-equilibrated ion exchange resin to form a shelf stable coateddrug-resin complex.

The present invention provides a method of forming a sustained-releasecoated pharmaceutical drug-ion exchange resin composition by applying apharmaceutically active drug directly to a non-equilibrated ion exchangeresin to form a drug-resin complex and apply a coating to the drug-resincomplex. The drug-resin complex is shelf stable.

The present invention provides a pharmaceutical composition made by theprocess of loading one or more drugs in a solution onto one or more ionexchange resin particles to form drug-loaded resin particles. Thedrug-loaded resin particles are separated from the solution and dried.The drug-loaded resin particles are recombined with the drug solutionand more of the drug is loaded onto the drug-loaded resin particles.

The present invention provides a method of making a pharmaceuticalcomposition by loading, in a solution, one or more substances onto oneor more cationic exchange resin particles to form a loaded resinparticle. One or more sugar alcohols (e.g., between about 0.01% to about10% by weight) are added to the solution to make prior to separating theloaded resin particle from the solution. The loaded resin particle isdried and recombined with the solution to load more drugs onto thedrug-loaded resin particle.

In addition, the present invention provides a method of making adrug-resin compound by loading one or more drugs onto one or more ionexchange resin particles in a solution to form a drug-loaded resinparticles. The drug-loaded resin particles are separated from thesolution and dried. The drugs solution is recombined with thedrug-loaded resin particles to add more drugs to the drug-loaded resinparticles. The drug-loaded resin particles are then dried.

The present inventors have recognized that the nature of the materialused as pharmaceutically acceptable ion exchange resins result in theresin undergoing significant swelling (e.g., up to about a 60% increasein volume) when the non-hydrated resin-drug complex is placed in contactwith fluids, e.g., water, biological fluid, gastrointestinal fluids.When an ion exchange resin-drug complex is coated with a water-permeablediffusion barrier the swelling of the ion exchange resin often rupturesthe diffusion barrier coating. The damage to the water-permeablediffusion barrier coating results in a loss of control of the rate ofdiffusion of the drug from the resin-drug complex. In addition, theswelling of the ion exchange resin affects the dimensions and shape ofthe ion exchange resin-drug complex. Additionally, the coating can peelfrom the resin-drug complex.

The present inventors have recognized that prior art methods teachtreating the ion exchange resin-drug complexes with an impregnatingagent, e.g., polyethylene glycol, propylene glycol, mannitol, lactose,methylcellulose or propylene glycol to reduce the swelling of ionexchange resins. However, the amount of impregnating agents used tocontrol the swelling is dependent on a variety of factors (e.g., thepolymer, the solvent composition, the salt concentration, the polarityof the solvent, the degree of cross-linking, the exchange capacity, thestrong or weak salvation tendency of the ion groups, the size and extentof the solvation of counter ions, the concentration of the externalsolution, the extent of the ionic dissociation of functional groups andso forth) and ranges from 15% to 40% by weight. For example, oneformulation currently used includes AMBERLITET® IR-120phenylpropanolamine complex with a 35% drug loading treated withpolyethylene glycol 4000 at about 30 parts by weight of the solvatingagent to 100 parts by weight of the resin to reduce swelling.

Specifically, the use of glycols to control the swelling of ion exchangeresin drug complexes offers many disadvantages. For instance, theconcentration of glycol must be between 15% to 40% by weight to controlthe swelling of the ion exchange resin drug complexes; however, evenwith such concentrations of glycol, there remains swelling of the ionexchange resins drug complex. Furthermore, many compounds are notcompatible with glycols, e.g., penicillin, bicitracine, iodine,potassium iodide, tannic acid, and bismuth salts.

In accordance with the present invention, a method and composition areprovided that include an ion exchange resin treated with from about 0.1%to about 10% by weight of one or more sugar alcohols in contact with oneor more ionic pharmaceutically active compounds. Specifically, the ionexchange resin is a cationic exchange resin treated with less than fivepercent sorbitol to control the subsequent swelling of the drug-resincomplex while maintaining a low concentration of impregnating agents.

For example, the present invention includes a pharmaceutical compositionhaving a pharmaceutically active substance in communication with an ionexchange resin that is treated with from about 0.01% to about 10% byweight of one or more sugar alcohols.

In accordance with the present invention, a method is provided thatreduces the swelling of a pharmaceutical composition by contacting oneor more cationic exchange resin particles with a solution containingfrom about 0.01% to about 10% by weight of sugar alcohol, based on thecombined weight of the sugar alcohol and the one or more ionic exchangeresin particles.

In addition, the present invention includes a method of preparing apharmaceutical ion exchange resin drug complex that does not requirewashing. The method includes contacting one or more grossly wettedcationic exchange resin particles with a drug and adding about 0.01% toabout 10% by weight of one or more sugar alcohols, based on the combinedweight of the sugar alcohol, the drug and the one or more grossly wettedionic exchange resin particles.

In addition, the present invention provides a sustained-release coated,layered pharmaceutical drug-ion exchange resin composition. The layeredpharmaceutical drug-ion exchange resin composition includes a firstpharmaceutically active drug applied directly to a non-equilibrated ionexchange resin to form a first drug-resin complex. One or more secondpharmaceutically active drugs are applied directly to the firstdrug-resin complex to form a second layer of pharmaceutically activedrugs and a layered drug-resin complex. A coating is applied to thelayered drug-resin complex wherein the layered-drug-resin complex isshelf stable.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures and in which:

FIG. 1 is a graph of the release profile of phenylephrine hydrochloridefrom DRC; and

FIG. 2 is a graph of the release profile for hydrocodone/resin preparedby the present invention this invention.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

A number of definitions are provided herein to facilitate anunderstanding of the present invention. As used herein, the term“pharmaceutical composition” also describes a solution, suspension,cream, ointment, lotion, capsule, caplet, softgel, gelcap, suppository,enema, elixir, syrup, emulsion, film, granule, gum, insert, jelly, foam,paste, pastille, pellet, spray, troche, lozenge, disk, magma, poultice,or wafer and the like.

As used herein, the term “sugar alcohol,” “organic polyol,” “polyhydricalcohol,” “polyalcohol” or “polyol” are used interchangeably to describenon-toxic C2 to C12 linear or branched hydrocarbon having at least 2hydroxy groups, non-toxic C5 to C12 cyclic or heterocyclic hydrocarbonhaving at least 2 hydroxy groups, e.g., sorbitol, mannitol,polyglycitol, maltitol, lactitol, isomalt, erythritol, glycerin,polydextrose, fructose, maltose xylitol, 1,3-dihydroxypropane inositoland the carbohydrates such as glucose, sucrose.

As used herein, a “prodrug” is a compound that metabolizes or otherwiseconverts from an inactive, nontoxic compound to a biologically,pharmaceutically, therapeutically active form of the compound. A prodrugmay also be a pharmaceutically inactive compound that is modified uponadministration to yield an active compound through metabolic or otherprocesses. The prodrug may alter the metabolic stability or thetransport characteristics of a drug, mask side effects or toxicity,improve or alter other characteristics or properties of a drug. Byvirtue of knowledge of pharmacodynamic processes and drug metabolism invivo, those of skill in this art, once a pharmaceutically activecompound is known, can design inactive forms of the compound (see, e.g.,Nogrady, Medicinal Chemistry A Biochemical Approach, Oxford UniversityPress, New York, pages 388-392, 1985).

The term “immediate release” is used herein to describe a releaseprofile to effect the delivery of an active ingredient as soon aspossible, that is, as soon as practically made available to a subject,whether in active form, as a precursor and/or as a metabolite. Immediaterelease may also be defined functionally as the release of over 80% to90% of the active ingredient within about 60, 90, 100 or 120 minutes orless. Immediate release as used herein may also be defined as making theactive ingredient available to the subject regardless of uptake, as somedrugs may never be absorbed by the animal. Immediate releaseformulations of the active on a carrier, such as rolled or compressedbeads, may be formulated such that the surface area is maximized onbeads and the active ingredient is exposed immediately. Variousimmediate release dosage forms may be designed readily by one of skillin art to achieve drug delivery to the stomach and small intestine,depending upon the choice of compression, adhesive materials and/orbeading.

The terms “extended-release,” “controlled-release” and “delayed-release”as used herein define a release profile to effect delivery of an activeingredient over an extended period of time, defined herein as beingbetween about 60 minutes and about 2, 4, 6 or even 24 hours.Extended-release may also be defined functionally as the release of over80% to 90% of the active ingredient after about 60 minutes and about 2,4, 6 or even 8 hours. Extended-release as used herein may also bedefined as making the active ingredient available to the subjectregardless of uptake, as some drugs may never be absorbed by thesubject. Various extended and delayed-release dosage forms may bedesigned readily by one of skill in art as disclosed herein to achievedelivery to both the small and large intestines, to only the smallintestine, or to only the large intestine, depending upon the choice ofcoating materials and/or coating thickness. As used herein, “a subject”is a patient, animal, insect, mammal or human who will benefit from themethod of this invention.

Pharmaceutical compositions designed for sustained-release of activedrugs and taste masking commonly use ion exchange resins particles. Thepresent invention provides controlled-release pharmaceuticalcompositions obtained by complexing a drug with a pharmaceuticallyacceptable ion-exchange resin, treating with a sugar alcohol and in somecases coating the complex with a substance that will act as a barrier tocontrol the diffusion of the drug from its core complex into thegastrointestinal fluids.

For example, the present invention provides a method and compositionthat control the swelling of an ion exchange resin particle with one ormore ionic pharmaceutically active drugs that includes treating withfrom about 0.01% to about 10% by weight of one or more sugar alcohols.

The ion exchange resin particles and pharmacological drug are mixed inan aqueous solution, dried and coated with a water-permeable diffusionbarrier. Sorbitol is added to the ion exchange resin-drug complex tocontrol the swelling of the ion exchange resins drug complex uponcontact with bodily fluids and in turn reducing the rupturing andpeeling of the coating.

For example, a pharmaceutical composition may have an ionicpharmaceutically active drug that is in communication with an ionexchange resin, wherein the ionic exchange resin has been treated withone or more sugar alcohols of between about 0.01% and about 10% byweight, based on the combined weight of the one or more sugar alcoholsand the complex particles. Optionally, the pharmaceutical compositionmay be coated with a water-permeable diffusion barrier coating, wherebya selective, prolonged continuous release of the drug is obtainableunder conditions encountered in the gastrointestinal tract.

The present invention includes a pharmaceutical grade cationicion-exchange resin to bind anionic molecules. Ion exchange resins can bedescribed simply as insoluble polymers that contain ionizable groupsdistributed regularly along the polymer backbone. As a consequence, anycounter ion (e.g., drug) associated with the ion exchange resin isionically bound to the ion exchange resin and physically separated fromthe surrounding fluid.

The cationic exchange resin of the present invention may be strongly orweekly acidic and have a variety of functional groups, e.g., weaklyacidic type of resin containing carboxylic acid group, or stronglyacidic type of resin containing sulfonic functional groups. Generally,the carboxylic functional groups are derived from polymers or copolymersof methacrylic acid or polymethacrylic acid and the sulfonic functionalgroups are generally derived from polymers or copolymers of styrene anddivinylbenzene. Other polymeric matrices, organic ion exchange matricesor inorganic ion exchange matrices may be used as suitable ion exchangeresins, e.g., methacrylic, acrylic and phenol formaldehyde.

In addition, ion exchange agents may be used in conjunction with polymermatrices (e.g., cellulosic or dextran) to form a suitable ion exchangeresin. In one embodiment of the present invention, the ionic exchangeresin is a sulfonic acid cationic exchange resin. The present inventionalso uses a sulphonic acid cation exchange resin, which includesphenol-sulphonic acid cation exchange resins and carboxylic-sulphonicacid cation exchange resins. Generally, the resin salt is obtained fromthe reaction of a sulphonic acid with an alkali, e.g., amine. The basicsulphonic acid cation exchange resin has a cation of an amphetamineadsorbed thereon. The skilled artisan will recognize that other cationicexchange resins may be used.

Similarly, a wide range of cationic (for the basic drugs) or anionic(for the acidic drugs) exchange resins can be used to form ion exchangeresin drug complexes. In general, ion-exchangers suitable for use inion-exchange chromatography and for such applications as deionization ofwater are suitable for use as controlled-release drug preparations. Forexamples, a model large ion exchange particle includes the cationicexchange resin AMBERLITE® IR-120 having a 20-30 mesh spherical particlesand a model small ion exchange particle resin includes AMBERLITET® XE-69with a 100-200 mesh fractured resin particles of AMBERLITE® IR-120. Theparent resin of AMBERLITE® IR-120 and AMBERLITE® XE-69 is described bythe manufacturer as gel-type divinylbenzene sulfonic acid cationexchange resin that swells in water. Other suitable ion exchange resincandidates include synthetic ion exchange resins with differentpolymeric matrices (e.g., methacrylic, acrylic, phenol formaldehyde),ion exchange agents with cellulosic or dextran polymer matrices andinorganic ion exchange matrices.

The ionic exchange resin includes sulfonic acid cationic exchange resinsand may be made from a polyester polymer containing sulphonic groups,additionally containing units derived from ethylene glycol, unitsderived from tri- and tetraethylene glycol and units derived fromterephthalate, neutralized polyesters having a terminal amine functionalgroup, polyester block copolymers, block copolymers of phthalic andsulphonphthalic acid/ethylene glycol/polymethyl siloxane α,γ-hydroxypropyl and vinyl acetate/vinyl butylbenzoate/crotonic acid. Inaddition, the polymer resin may be cross-linked. The cross-linkersinclude poly(2-acrylamido-2-methylpropanesulphonic acid) polymer withone monomer containing at least two olefinic double bonds, e.g.,dipropylene glycol diallyl ether, polyglycol diallyl ether, triethyleneglycol divinyl ether, hydroquinone diallyl ether, tetraallyloxyethanoyl,allyl ether, vinyl ether, a polyfunctional alcohol, tetraethylene glycoldiacrylate, triallylamine, trimethylolpropane diallyl ether,methylenebisacrylamide or divinylbenzene.

Representative pharmaceutical grade ion exchange resins for use inaccordance with the present invention are known to those skilled in theart. For example, pharmaceutical grade ion exchange resins arecommercially available, e.g., the Rohm and Haas company and Dow Corning,e.g., AMBERLITE® IR-20, AMBERLITE® IRP-69, AMBERLITE® IRP-64, AMBERLITE®IRP-58, AMBERLITE® IRC-50, AMBERLITE® IRP-69 and DOW® XYS-40010.00, DOW®XYS-40013.00, etc. The pharmaceutical grade cationic ion-exchange resinsmay include particles of varying size ranges, and as either amonodisperse or a polydisperse mixture. The ion exchange resin particlesmay range in size from 40 to 1500. In one example, the gel-typedivinylbenzene sulfonic acid cation exchange resin AMBERLITE® IRP-69consisting of 100-200 mesh was used.

In general, all acidic and basic drugs, especially those having shortbiological half-lives in the order of up to about 12 hours, arepotential candidates for inclusion in the present invention. Many drugsexist in the free acid, free base, and a salt form. For example, a basedrug may exist as either a free base form or a salt form, e.g.,lidocaine, a base drug, with an amine free base form and a hydrochlorideacid-addition salt form. Conversely, an acid drug may exist in either afree acid form or in the form of a salt made by reacting the free acidwith a base, e.g., salicylic acid exists as a salt, typically as sodiumsalicylate. For example, a cationic resin interacts with the basicnitrogen group of an organic molecule. Generally, the functional groupson the drug dictate the interaction with the ion exchange resin, andthus, influence the adsorption and the elution characteristics of thedrug. A substantial portion of the active drug is adsorbed within thepolymer matrix of the ion exchange resin and elutes therefrom. Tocontrol the elution rate, the size of the particle and the size of theadsorbed drug may be altered by modifying the cross linkage of the ionexchange resin.

Suitable pharmaceutically active drugs include narcotic analgesics,(e.g., codeine, dihydrocodeine, hydromorphone, morphine, pentazocine andpropoxyphene), sympathomimetics, (e.g., norephedrine andpseudoephedrine), antitussives, (e.g., dextromethorphan, gauifenesin),analgesics, (e.g., aspirin and tramadol), antiemetics, (e.g.,metoclopramide), anticholinergics, (e.g., atropine, ipratropium bromideand scopolamine), muscle relaxants, (e.g., cyclobenzaprine andpapaverine), bronchodilators, (e.g., salbutamol, terbutaline andtheophylline), antibiotics, (e.g., amoxycillin, ampicillin, azlocillin,bacampicillin, cefamandole, cefonicid, cefotaxime, cefotetan, cefoxitin,ceftriaxone, mezlocillin and piperacillin), antidepressants, (e.g.,bupropion, nomifensine, and nortriptyline), antiasthmatics, (e.g.,cromolyn), antineoplastics, (e.g., tamoxifen), antiepileptics, (e.g.,valproic acid and phenvtoin), cardiovascular agents, (e.g., propranolol)phenylephrine, and gauifenesin. Acid addition salts or, if appropriate,alkali or alkaline earth metal salts of the above drugs would beparticularly suitable for use in the present invention.

Specific examples of suitable pharmaceutically active drugs include, butare not limited to, dehydrocholic acid, diflunisal, ethacrynic acid,fenoprofen, furosemide, gemfibrozil, ibuprofen, naproxen, phenytoin,probenecid, sulindac, theophylline, salicylic acid, acetylsalicylicacid, acetophenazine, amitriptyline, amphetamine, benztropine,biperiden, bromodiphenhydramine, brompheniramine, carbinoxamine,chlorcyclizine, chlorpheniramine, chlorphenoxamine, chlorpromazine,clemastine, clomiphene, clonidine, codeine, cyclizine, cyclobenzaprine,cyproheptadine, desipramine, desloratadine, dexbrompheniramine,dexchlorpheniramine, dextroamphetamine, dextromethorphan, dicyclomine,diphemanil, diphenhydramine, doxepin, doxylamine, ergotamine,fluphenazine, haloperidol, hydrocodone, hydroxychloroquine, hydroxyzine,hyoscyamine, imipramine, levopropoxyphene, loratadine, maprotiline,meclizine, mepenzolate, meperidine, mephentermine, mesoridazine,methadone, methdilazine, methscopolamine, methysergide, metoprolol,nortriptylene, noscapine, nylindrin, orphenadrine, papaverine,pentazocine, phendimetrazine, phentermine, phenylephrine,phenylpropanolamine, pyrilamine, tripelennamine, triprolidine,promazine, propoxyphene, propanolol, pseudoephedrine, pyrilamine,quinidine, scopolamine, dextromethorphan, chlorpheniramine, codeine,aminocaproic acid, aminosalicylic acid, hydromorphone, isoxsuprine,levorphanol, melphalan, morphine, nalidixic acid, paraaminosalicylicacid and mixtures and combinations thereof.

Examples of acidic and basic drugs that may be used with the presentinvention include phenylpropanolamine (PPA), dextromethorphan, ephedrin,pseudoephedrine, paraamino salicyclic acid, acetyl salicylic acid,phentermine (phenyl-tertiary-butyl-amine) and acetaminophen. The skilledartisan will recognize the variety of drugs and resins that may be usedand the modifications to alter the polymer, copolymer, cross linkingagent that may be used to alter the characteristics of the drug-resincomplex. The pharmaceutically active compounds useful in the practice ofthe present invention include antihistamines, decongestants,antitussives and/or expectorants. Other drugs for use with the presentinvention include, but are not limited to, non-steroidalanti-inflammatory drugs (NSAIDs) and other analgesic drugs, e.g.,acetaminophen and phenacetin. These materials are incorporated into theimmediate or controlled-release formulations of the invention in amountsgoverned by the desired release characteristics of the material in suchexcipient base and such that conventional dosages comply with applicableFDA or other regulations. The drug may be loaded in a specificconcentration to allow the specific release of the drug over a giventime range. In general, the maximum concentration of bound drug may bein excess of about 60%; however, ranges between about 1% and about 50%are contemplated with the present invention.

The present invention may be used to deliver bioactive agents includingpharmaceuticals and drugs, bioactive synthetic organic molecules,genetic materials, proteins, peptides, polypeptides, vitamins, steroids,polyanionic agents, genetic material, and diagnostic agents. Bioactivevitamins, steroids, proteins, peptides and polypeptides can be ofnatural origin or synthetic. Exemplary polyanionic agents include, butare not limited to, sulphated polysaccharides, negatively charged serumalbumin and milk proteins, synthetic sulphated polymers, polymerizedanionic surfactants, and polyphosphates. Suitable diagnostic agentsinclude, but are not limited to, dyes and contrast agents for use inconnection with magnetic resonance imaging, ultrasound or computedtomography of a patient. In addition, the pharmaceutically active drugmay be any pesticide known to the skilled artisan for use in theextended-release pesticide control of insects, rodents and other pests.

Suitable genetic material includes nucleic acids, nucleosides,nucleotides, and polynucleotides that can be either isolated genomic,synthetic or recombinant material; either single or double stranded; andeither in the sense or antisense direction, with or withoutmodifications to bases, carbohydrate residues or phosphodiesterlinkages. Exemplary sources for the genetic material include, but arenot limited to, deoxyribonucleic acids (DNA), ribonucleic acids (RNA),complementary DNA (cDNA), messenger RNA (mRNA), ribosomal RNA (rRNA),short interfering RNA (siRNA), ribozymes, and mixed duplexes andtriplexes of RNA and DNA.

Genetic materials are genes carried on expression vectors including, butnot limited to, helper viruses, plasmids, phagemids, cosmids, and yeastartificial chromosomes. The genetic material suitable for the presentinvention is capable of coding for at least a portion of a therapeutic,regulatory, and/or diagnostic protein. Moreover, genetic materials canpreferably code for more than one type of protein. For example, abioactive agent may include plasmid DNA having genetic material encodingtherapeutic protein and a selectable or diagnostic marker to monitor thedelivery of the plasmid DNA, e.g., pDsRed-human insulin promoter. Suchproteins include, but are not limited to, histocompatibility antigens,cell adhesion molecules, growth factors, coagulation factors, hormones,insulin, cytokines, chemokines, antibodies, antibody fragments, cellreceptors, intracellular enzymes, transcriptional factors, and toxicpeptides capable of eliminating diseased or malignant cells. Othergenetic materials that could be delivered by this technique includedadenovirus, adeno-associated virus, retrovirus, lentivirus, RNA, siRNA,or chemicals that selectively turn on or off specific genes, such aspolyamides or peptide fragments. Modifications to wild-type proteinsresulting in agonists or antagonists of the wild type variant fall inthe scope of this invention. The genetic material may also include atissue-specific promoter or expression control sequences such as atranscriptional promoter, an enhancer, a transcriptional terminator, anoperator or other control sequences.

Examples of active agents for use with the present invention include,but are not limited to, hormone products; vasopressin and oxytocin andtheir derivatives, glucagon and thyroid agents; iodine products;anti-thyroid agents; cardiovascular products; chelating agents;mercurial diuretics; cardiac glycosides; respiratory products; xanthinederivatives (e.g., theophylline and aminophylline); anti-infectives;aminoglycosides, antifungals (e.g., amphotericin); penicillin;cephalosporin antibiotics; antiviral agents (e.g., zidovudine,ribavirin, amantadine, vidarabine and acyclovir); antihelmintics;antimalarials; and antituberculous drugs; biologicals such as antibodies(e.g., antitoxins and antivenins), vaccine antigens (e.g., bacterialvaccines, viral vaccines, toxoids); antineoplastics (e.g., nitrosoureas,nitrogen mustards, antimetabolites (fluorouracil, hormones, progestinsand estrogens agonists and/or antagonists); mitotic inhibitors (e.g.,etoposide and/or vinca alkaloids); radiopharmaceuticals (e.g.,radioactive iodine and phosphorus products); and interferon;hydroxyurea; procarbazine; dacarbazine; mitotane; asparaginase andcyclosporins, including mixtures and combinations thereof.

Other suitable therapeutics include, but are not limited to:thrombolytic agents such as urokinase; coagulants, e.g., thrombin;antineoplastic agents, such as platinum compounds (e.g., spiroplatin,cisplatin, and carboplatin), methotrexate, adriamycin, taxol, mitomycin,ansamitocin, bleomycin, cytosine arabinoside, arabinosyl adsnine,mercaptopolylysine, vincristine, busulfan, chlorambucil, melphalan(e.g., PAM, L-PAM or phenylalanine mustard), mercaptopurine, mitotane,procarbazine hydrochloride dactinomycin (actinomycin D),daunorubicinhydrochloride, doxorubicin hydrochloride, mitomycin,plicamycin (mithramycin), aminoglutethimide, estramustine phosphatesodium, flutamide, leuprolide acetate, megestrol acetate, tamoxifencitrate, testolactone, trilostane, amsacrine (m-AMSA), asparaginase(L-asparaginase), erwinaasparaginase, etoposide (VP-16), interferonalpha-2a, interferon alpha-2b, teniposide (VM-26), vinblastine sulfate(VLB), vincristine sulfate, bleomycin, bleomycin sulfate, methotrexate,adriamycin, and arabinosyl; blood products such as parenteral iron,hemin; biological response modifiers such as muramyldipeptide,muramyltripeptide, microbial cell wall components, lymphokines (e.g.,bacterial endotoxin such as lipopolysaccharide, macrophage activationfactor), sub-units of bacteria (e.g., Mycobacteria, Corynebacteria), thesynthetic dipeptide N-acetyl-muramyl-L-alanyl-D-isog- lutamine;anti-fungalagents such as ketoconazole, nystatin, griseofulvin,flucytosine (5-fc), miconazole, amphotericin B, ricin, and beta-lactamantibiotics (e.g., penicillin, ampicillin, sulfazecin); hormones such asgrowth hormone, PDGF, EGF, CSF, GM-CSF, melanocyte stimulating hormone,estradiol, beclomethasone dipropionate, betamethasone, betamethasoneacetate and betamethasone sodium phosphate,vetamethasonedisodiumphosphate, vetamethasone sodium phosphate,cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasonesodium phosphate, flunsolide, hydrocortisone, hydrocortisone acetate,hydrocortisone cypionate, hydrocortisone sodium phosphate,hydrocortisone sodium succinate, methylprednisolone, methylprednisoloneacetate, methylprednisolone sodium succinate, paramethasone acetate,prednisolone, prednisoloneacetate, prednisolone sodium phosphate,prednisolone rebutate, prednisone, triamcinolone, triamcinoloneacetonide, triamcinolone diacetate, triamcinolone hexacetonide andfludrocortisone acetate; vitamins (e.g., vitamin C, E, A, K),ascyanocobalamin, neinoic acid, retinoids and derivatives such asretinolpalmitate, and alpha-tocopherol(s); peptides (e.g., T cellepitopes such as MAGE, GAGE, DAGE, etc.); proteins, such as manganesesuper oxide dimutase, alcohol dehydrogenase, nitric oxide synthase;enzymes such as alkaline phosphatase; anti-allergic agents such asamelexanox; anti-coagulation agents such as phenprocoumon and heparin;circulatory drugs such as propranolol; metabolic potentiators suchasglutathione; antituberculars such as para-aminosalicylic acid,isoniazid, capreomycin sulfate cycloserine, ethambutol hydrochlorideethionamide, pyrazinamide, rifampin, and streptomycin sulfate;antivirals such as acyclovir, amantadine azidothymidine (AZT orZidovudine), Ribavirin andvidarabine monohydrate (adenine arabinoside,ara-A); antianginals such asdiltiazem, nifedipine, verapamil, erythrityltetranitrate, isosorbidedinitrate, nitroglycerin (glyceryl trinitrate)and pentaerythritoltetranitrate; anticoagulants such as phenprocoumon,heparin; antibiotics such as dapsone, chloramphenicol, neomycin,cefaclor, cefadroxil, cephalexin, cephradine erythromycin, clindamycin,lincomycin, amoxicillin, ampicillin, bacampicillin, carbenicillin,dicloxacillin, cyclacillin, picloxacillin, hetacillin, methicillin,nafcillin, oxacillin, penicillin G, penicillin V, ticarcillin rifampinand tetracycline; antiinflammatories such as difunisal, ibuprofen,indomethacin, meclofenamate, mefenamic acid, naproxen, oxyphenbutazone,phenylbutazone, piroxicam, sulindac, tolmetin, aspirin and salicylates;antiprotozoans such as chloroquine, hydroxychloroquine, metronidazole,quinine and meglumine antimonate; antirheumatics such as penicillamine;narcotics such as paregoric; opiates such as codeine, heroin, methadone,morphine and opium; cardiac glycosides such as deslanoside, digitoxin,digoxin, digitalin and digitalis; neuromuscular blockers such asatracurium besylate, gallamine triethiodide, hexafluorenium bromide,metocurine iodide, pancuronium bromide, succinylcholine chloride(suxamethonium chloride), tubocurarine chloride and vecuronium bromide;sedatives (hypnotics) such as amobarbital, amobarbital sodium,aprobarbital, butabarbital sodium, chloral hydrate, ethchlorvynol,ethinamate, flurazepam hydrochloride, glutethimide, methotrimeprazinehydrochloride, methyprylon, midazolam hydrochloride, paraldehyde,pentobarbital, pentobarbital sodium, phenobarbital sodium, secobarbitalsodium, talbutal, temazepam and triazolam; local anesthetics such asbupivacaine hydrochloride, chloroprocaine hydrochloride,etidocainehydrochloride, lidocaine hydrochloride, mepivacainehydrochloride, procainehydrochloride and tetracaine hydrochloride;general anesthetics such asdroperidol, etomidate, fentanyl citrate withdroperidol, ketaminehydrochloride, methohexital sodium and thiopentalsodium; and radioactive particles or ions such as strontium, iodiderhenium and yttrium, and combinations and mixtures thereof

The ion exchange resin of the present invention is treated with one ormore sugar alcohols. The ion exchange resin may be treated before,during or after the addition of the pharmaceutical drug and formation ofthe drug-resin complex. Additionally, the drug-resin complex may betreated before, during or after the addition of a coating to thedrug-ion exchange resin complex. The sugar alcohol may be added as asolid, liquid, gas or gel. The sugar alcohols may be in an aqueoussolution or mixtures containing varying amounts of organic compoundsknown to those skilled in the art. Furthermore, when more than one sugaralcohol is used, the sugar alcohols may be similar or differentdepending on the particular application and conditions. In someembodiments, the ionic exchange resin may be treated with between about1% to 10% by weight of sorbitol, based on the combined weight of thesorbitol and the drug-resin particles. Other concentrations of sorbitolmay be used including about 0.1% to about 5% by weight.

The sugar alcohols may be of many types known to persons of skill in theart to control the swelling of the pharmaceutical grade ion exchangedrug-resins complex. The sugar alcohol is generally sorbitol; however,polyhydric alcohols such as mannitol; sorbitol; xylitol; maltitol;lactitol, 1,3-dihydroxypropane, or other non-toxic C2 to C12 linear orbranched hydrocarbon having at least 2 hydroxy groups known to theskilled artisan may be used. Additionally, non-toxic C5 to C12 cyclic orheterocyclic hydrocarbon having at least 2 hydroxy groups (e.g.,inositol and the carbohydrates such as glucose, sucrose) may be used aswell. The sugar or the sugar alcohol present in the solution has amolecular weight of from 90 to 550, and especially from molecularweights of between 150 and 370. The sugars are monosaccharides ordisaccharides and reduced monosaccharides or disaccharides andsubstituted monosaccharides or disaccharides. Suitable sugars/sugaralcohols are sucrose, dextrose, maltose, fructose, lactose, mannitol,sorbitol or xylitol.

The general method for preparing controlled-release cationic exchangeresin drug complex using the present invention involves: (i) preparationof an ion exchange resin drug complex; (ii) treating the ion exchangeresin drug complex with a suitable sugar alcohol; and (iii) drying thetreated ion exchange resin drug complex. The ion exchange resin drugcomplex may be optionally coated with a water-permeable diffusionbarrier.

Preparing the ion exchange resin drug complex from the ion exchangeresin generally includes mixing the ion exchange resin with a solutionin the presence of a polyalcohol and allowing sufficient time forloading. The resin/fluid slurry is filtered. Unlike methods currentlyused in the art, it is not necessary to wash the ionic exchangeresin-complex after the additions. Furthermore, the present inventionprovides for equilibrium redistribution by allowing the unbound drug,the free drug or any water soluble swelling agent to redistribute inequilibrium. The equilibrium distribution allows the free drug to befurther taken up by the resin.

For example, the present invention includes a method of making apharmaceutical composition by contacting one or more ion exchange resinparticles and one or more pharmaceutically active drugs to form acationic exchange resin pharmaceutically active drugs complex. The ionicexchange resin drug complex is treated to control the swelling of theresin by adding one or more sugar alcohols. The one or more sugaralcohols make up between about 0.01% and about 10% by weight of one ormore sugar alcohols, based on the combined weight of the sugar alcohol,the drug(s) and the one or more ionic exchange resin particles. Thecomposition may then be formulated into the desired pharmaceuticalcomposition delivery forms.

Generally, the present invention is formulated into a liquid, gel,tablet, caplet, or capsule; however, other pharmaceutical compositiondelivery forms may be used while taking advantage of the presentinvention. Other agents may be added including binders, lubricants,diluents, disintegrating agents, coloring agents, sweeteners, flavoringagents, preservatives and flow-inducing agents. The tablets can becompressed, multiple compressed, tablet triturates or coated, e.g.,enteric coating, sugar coating, or film coating. When in the form of aliquid, the liquid oral dosage may be in the form of aqueous andnon-aqueous solutions, emulsions, suspensions, and solutions granules,containing suitable, emulsifying agents, solvents, preservatives,suspending agents, diluents, sweeteners, coloring agents, and flavoringagents.

The present invention provides a method of preparing a resin drugcomplex without washing. Preparing the ion exchange resin drug complexfrom the ion exchange resin includes mixing the ion exchange resin witha solution and allowing sufficient time for loading. The resin/fluidslurry is filtered. Unlike methods currently used in the art, it is notnecessary to wash the ionic exchange resin-complex.

The present invention also provides a method of controlling the swellingof a pharmaceutical composition by contacting one or more cationicexchange resin particles with about 0.01% to about 10% by weight ofsugar alcohol, based on the combined weight of the sugar alcohol, thedrug(s). In accordance with the present invention, it is necessary tocombine the sugar alcohol with the ion exchange resin to form a mixture(e.g., slurry). Generally, the mixture is an aqueous solution; however,other solutions, compositions or mixtures are acceptable. The ratio ofion exchange resin to sugar alcohol is from about 1:1 to about 50:1,i.e., from about 1 gram of resin per gram of the sugar alcohol to about1 gram of resin per 20 mg. of polyol. Other ratios may be used dependingon the method of incorporation and the particular sugar alcohol andresin, e.g., about 1:0.01 to about 5:0.01, about 0.01:1 to about 0.01:5,and combinations thereof. In Example I, the ratio of the amount of ionexchange resin in suspension to the amount of sugar alcohol is about1.7:1 (e.g., 300 gram of resin per 175 gram of molecule) with most ofthe sugar alcohol not remaining in the product. In another example, theconcentration of the sugar alcohol is between about 1% and 10% byweight, i.e., about 10 mg to about 100 mg of molecule.

EXAMPLE I Resin 300 g Drug 300 g 70% Sorbitol 250 mL Purified Water 750mL

In Example I, the water, sorbitol, drug and resin are slurried togetherand sufficient time is allowed for the drug to load onto the resin. Whenthe loading operation is completed, the components of the slurry areseparated (e.g., filtered or centrifuged) into liquid and solidfractions. Because the sugar alcohol is highly water soluble, most ofthe sugar alcohol remains in the aqueous phase, leaving about 4%sorbitol in the solids. The solids are not washed but are dried to yieldmaterial suitable for coating.

EXAMPLE II Resin 300.0 g Drug 300.0 g Sorbitol  7.5 g Purified Water992.5 mL

In Example II, the water, drug and resin are slurried together andsufficient time is allowed for the drug to load onto the resin. When theloading operation is completed, the slurry is separated (e.g., filteredor centrifuged) into liquid and solid fractions. The liquid fraction isdiscarded. The solid fraction is not washed but is dried. Sorbitol isdissolved in 100 grams water, added to the dried drug-resin complex andthe drug-resin complex is allowed to absorb the sorbitol solution. Thetreated resin may then be dried and coated.

To form the cationic exchange resin drug complex, it is necessary tocombine an ion exchange resin with one or more molecules, e.g., one ormore ionic drug compounds. The adsorption of molecules to the surface ofa resin is well known to persons of skill in the art. In addition, theionic drug molecule may be attached to a linker that allows attachmentof the drug to the ion exchange resin via the linker. The combination ofion exchange resins and drug may be in the form of a slurry or othermixture, depending on the particular application. In addition, a coatingmay be applied to the drug-resin complex. The mixture (e.g., anadmixture of a slurry of the ion exchange resin, the drug and the sugaralcohol) may be dried to remove the water. The drying may be carried outusing methods know to the skilled artisan, including conventional means,i.e., filtered, dried over a purge of nitrogen, under vacuum, in a fluidbed, in an oven, etc.

The present invention optionally includes a pharmacologically activedrug-resin complex coated to prolong the continuous release of drugsunder harsh biological conditions, e.g., such as those encountered inthe gastrointestinal tract. Conventional coating solvents (e.g.,ethanol, a methylene chloride/acetone mixture or other component knownto the skilled artisan) or aqueous based coatings and procedures can beemployed to coat the ion exchange resin drug complex. In oneillustrative example, air suspension spray coating techniques may becarried out using a Wurster coating apparatus. However, other techniquesmay be used to coat the particle, including other types of fluid bedspray, coacervation, solvent evaporation or other methods known topersons of skill in the art. Generally, the coating is applied to thedrug-resin complex. Alternatively, the coating can be applied to theresin before complexing with the drug.

Another example of a coated particle of the present invention provides aselective, prolonged continuous release of pharmacologically activedrugs under conditions such as those encountered in the gastrointestinaltract by the application of a diffusion barrier coating to an ionexchange drug-resin complex treated with a solvating agent. Anotherprolonged release formulation of the present invention includes theaddition of a second ionic substance (e.g., a combination drug, a dye, adispersing agent or the like) having the same ionic charge as the drugon the drug-resin complex by employing the second ionic substance in theion form of an exchange resin complex. The manufacture of a formulationof any drug for liquid dosage usage requires that the final formulationhave the drug dissolved or suspended in a liquid that possesses extendedshelf-life stability, exhibits no change in active drug dosage levelover a period of time and has acceptable taste. Thus, to prepare aliquid formulation of any type drug it may be necessary to employextenders such as water or syrup and to add flavors, sweeteners,thickening agents, dyes and the like. To control the dissolution profileof the formulation versus the dissolution profile of the same drug inwater, the coated particles may also be included in the presence ofionic substances bearing the same ionic charge as the sustained-releasedrug present in the formulation as a coated drug-resin complex. Thesecond ionic material need not be coated with the water-permeablediffusion barrier coating.

The water-permeable, diffusion barrier coating materials can be any ofthe conventional synthetic or natural film-forming materials withdiffusion barrier properties and with no inherent pharmacological ortoxic properties. For example, ethylcellulose, a water insolublefilm-forming agent, may be used as a diffusion barrier membranematerial. A plasticizer, (e.g., Durkex 500 vegetable oil) may be used toimprove the film forming characteristics of ethylcellulose and/or toalter the permeability characteristics of the film. The amount ofcoating used depends on the degree of drug release prolongation desiredand is a function of particle size, drug solubility, film permeabilityand other factors. By varying the amount of coating, and/or by blendingcoated drug-resin complex with uncoated drug-resin complex, and/orblending different coatings, it is possible to selectively modify thepreparation's drug dissolution profile as desired.

In general, the major components of the coating should be insoluble in,and permeable to, water. Alternatively, a water-soluble substance, suchas methyl cellulose, may be incorporated to alter the permeability ofthe coating, or an acid-insoluble, base-soluble substance to act as anenteric coating may be used. The water-permeable diffusion barrier willgenerally include a water insoluble material such as a wax, a fattyalcohol, shellac, zein, shellac, polyvinylpyrrolidone, a water insolublecellulose derivative, ethyl cellulose, a polymethacrylate, or methylcellulose. The coating materials may be applied as a solution orsuspension in an aqueous fluid or as a solution in organic solvents. Insome instances, the present invention may include a water-permeablediffusion barrier in contact with at least a portion of the ionicpharmaceutically active drug in communication with an ionic exchangeresin.

EXAMPLE III

The water-permeable diffusion barrier coated drug-resin complexincludes: Drug-resin Complex 2000 g Ethylcellulose  300 g Ethyl acetate5700 g

The drug-resin complex was placed in a fluid-bed coating apparatus andfluidized with intake air. The ethylcellulose was dissolved in the ethylacetate and applied at a rate of about 20-25 g/minute until 6000 g hadbeen applied. Fluidization was continued with the heated air for anadditional ten minutes after termination of the application of thecoating solution.

EXAMPLE IV

Another water-permeable diffusion barrier coated drug- resin complexincludes: Drug-resin Complex 2000 g Ethylcellulose  119 g Myvacet  11 gEthanol 2470 g

The drug-resin complex was placed in a fluid-bed coating apparatus andfluidized with intake air. The Myvacet was dissolved in the ethanol andthe ethylcellulose was dissolved in the Myvacet solution and applied ata rate of 20-25 g/minute until 2600 g of coating solution had beenapplied.

The present invention may be incorporated into a pharmaceuticalcomposition and include immediate release, extended-release ordelayed-release compositions. The present invention relates to oraladministration of cationic exchange resin drug complex, although otherdelivery methods are also contemplated, e.g., topical, rectal,injectable, subcutaneous, vaginal or nasal administration. Thepharmaceutical compositions of the present invention can take the formof tablets, powders, capsules, gels, hydro-gels, solids, lyophilizedsuspensions, liquid suspensions or other conventional dosage forms. Thepresent pharmaceutical composition may also be provided in a variety ofdosage forms, e.g., solution, suspension, cream, ointment, lotion,capsule, caplet, softgel, gelcap, suppository, enema, elixir, syrup,emulsion, film, granule, gum, insert, jelly, foam, paste, pastille,pellet, spray, troche, lozenge, disk, magma, poultice, or wafer and thelike. In addition, the resin-drug complex of the present invention issuitable for dosages varying over a wide range, e.g., from about 0.01 mgto about 2000 mg, depending on the nature of the drug, resin and itsintended usage.

In addition, the present invention may include other additivesconventionally used in pharmaceutical compositions and known to those ofskill in the art., e.g., anti-adherents, anti-sticking agents, glidants,flow promoters, lubricants, talc, magnesium stearate, fumed silica,micronized silica, surfactants, waxes, stearic acid, stearic acid salts,stearic acid derivatives, starch, hydrogenated vegetable oils, sodiumbenzoate, sodium acetate, leucine and magnesium lauryl sulfate.

In accordance with the present invention is a method of reducing thehandling of a pharmaceutical composition during preparation bycontacting one or more grossly wetted cationic exchange resin particleswith an active drug and adding about 0.1% to about 5% by weight of sugaralcohol, based on the combined weight of the sugar alcohol, drugsubstance and the one or more grossly wetted ionic exchange resinparticles. Additionally, the pharmaceutical composition can be coatedwith a water-permeable diffusion barrier.

EXAMPLE V

Purified Water USP 45.26 Kg Sorbitol USP  9.59 Kg AMBERLITE ® IRP6916.50 Kg Dextromethorphan HBr USP 16.50 Kg

In Example V, the water, sorbitol, drug and resin are slurried togetherand sufficient time is allowed for the drug to load onto the resin. Whenthe loading operation is completed the slurry is separated (e.g.,filtered or centrifuged) into liquid and solid fractions. Because thesugar alcohol is highly water soluble most of the sugar alcohol remainsin the aqueous phase leaving with about 4% sorbitol in the solids. Thesolids are not washed, but are dried to yield material suitable forcoating.

EXAMPLE VI

Purified Water USP 41.15 Kg Sorbitol USP (70%) 13.70 Kg AMBERLITE ®IRP69 16.50 Kg Pseudoephedrine HCl 16.50 Kg

In Example VI, the water, sorbitol, drug and resin are slurried togetherand time allowed for the drug to load onto the resin. When the loadingoperation is completed, the slurry is separated (e.g., filtered orcentrifuged) into liquid and solid fractions. Because the sugar alcoholis highly water soluble, most of the sugar alcohol remains in theaqueous phase leaving with about 4% sorbitol in the solids. The solidsare not washed but are dried to yield material suitable for coating.Product from examples V and VI were coated in fluidized bed processingunit using ethylcellulose plasticized with dibutyl sebacate fromacetone/alcohol solution. It is recognized that the release profile maybe modified by varying the coating level.

Release profiles for Examples V and VI are shown: Example V Example VITime Percent Released Percent Released  30 min 43% 50%  60 min 47% 55%180 min 53% 63% 360 min 57% 68%

Table I is an exemplary table of possible pharmaceutical compounds thatmay be used in conjunction with available resins. The skilled art willrecognize that other compounds may be used with the present inventionand that compounds may be modified or the particular chemical groupmodified in a compound to allow the use of that compound with thepresent invention. TABLE I Pharmaceutical compounds and drug-resins:Pharmaceutical Compounds Resins Codeine, Dihydrocodeine, Hydromorphone,AMBERLITE ® IR-20 Morphine, Pentazocine and Propoxyphene Norephedrineand Pseudoephedrine Dextromethorphan, gauifenesin, phenylephrine Aspirinand Tramadol, naprisin Metoclopramide Atropine, Ipratropium Bromide andScopolamine AMBERLITE ® IRC-50 Cyclobenzaprine and PapaverineSalbutamol, Terbutaline and Theophylline Amoxycillin, Ampicillin,Azlocillin, Bacampicillin, Cefamandole, Cefonicid, Cefotaxime,Cefotetan, Cefoxitin, Ceftriaxone, Mezlocillin and PiperacillinBupropion, Nomifensine, and Nortriptyline AMBERLITE ® IRP-58 CromolynValproic Acid and Phenvtoin Propranolol Tamoxifen Dehydrocholic Acid,Diflunisal, Ethacrynic Acid, AMBERLITE ® IRP-64 Fenoprofen, Furosemide,Gemfibrozil, Ibuprofen, Naproxen, Phenytoin, Probenecid, Sulindac,Theophylline, Salicylic Acid, Acetylsalicylic Acid, Acetophenazine,Amitriptyline, Amphetamine, Benztropine, Biperiden,Bromodiphenhydramine, Brompheniramine, Carbinoxamine, Chlorcyclizine,Chlorpheniramine, Chlorphenoxamine, Chlorpromazine, Clemastine,Clomiphene, Clonidine, Codeine, Cyclizine, Cyclobenzaprine,Cyproheptadine, Desipramine, Dexbrompheniramine, Dexchlorpheniramine,Dextroamphetamine, Dicyclomine, Diphemanil, Diphenhydramine, Doxepin,Doxylamine, Ergotamine, AMBERLITE ® XE-69 Fluphenazine, Haloperidol,Hydrocodone, Hydroxychloroquine, Hydroxyzine, Hyoscyamine, Imipramine,Levopropoxyphene, Maprotiline, Meclizine, Mepenzolate, Meperidine,Mephentermine, Mesoridazine, Methadone, Methdilazine, Methscopolamine,Methysergide, Metoprolol, Nortriptylene, Noscapine, Nylindrin,Orphenadrine, Papaverine, Pentazocine, AMBERLITE ® IR-120Phendimetrazine, Phentermine, Phenylpropanolamine, Pyrilamine,Tripelennamine, Triprolidine, Promazine, Propoxyphene, Propanolol,Pseudoephedrine, Pyrilamine, Quinidine, Scopolamine, Chlorpheniramine,Codeine, Aminocaproic Acid, Aminosalicylic Acid, Hydromorphone,Isoxsuprine, Levorphanol, Melphalan, DOW ® XYS-40013.00 Morphine,Nalidixic Acid, Paraaminosalicylic Acid Phenylpropanolamine (PPA),Dextromethorphan, Ephedrin, Pseudoephedrine, Paraamino Salicyclic Acid,Acetyl Salicylic Acid, Phentermine (Phenyl-Tertiary-Butyl-Amine) andAcetaminophen Acetominophen and Phenacetin DOW ® XYS-40010.00

The samples were evaluated under conditions that simulate thoseencountered in the gastrointestinal tract. The samples were evaluatedusing USP Dissolution Apparatus 2 and Simulated Gastric Fluid USP.Additional tests are applied as deemed suitable, i.e. USP Apparatus 4using Simulated Gastric Fluid or selected buffer solutions. The changesin absorption at the selected wavelength as a function of time wasrecorded as the drug was released from a drug-resin complex sample.

Table II is a comparison of the release curves in simulated gastricconditions for the present invention and resin complexes made by methodsused in the art. In Table II, the percent release is charted as afunction of time for the present invention (A), a sample made using thepost treatment protocol under U.S. Pat. No. 4,847,077 (B) and a samplemade using no treatment under the protocol of U.S. Pat. No. 4,996,047(C). The data represented in Table II demonstrates that while high drugloading can be used to prepare coated, slow-release drug-resincomplexes, the use of higher levels of treatment under the '077 patentresult in a slower, better controlled-release profile. It also showsthat much lower levels of treating agent as prepared by the presentinvention result in comparable, lower release rates. % Released Time(hours) A B C 0.1 14.3 18.3 19.3 0.5 29.3 29.1 32.5 1 33.9 33.1 37.5 237.9 36.9 41.6 3 40.3 39.1 44.1 4 42.1 41.0 45.6 5 43.6 42.3 47.2 6 44.843.7 48.8 7 45.9 44.3 49.7 8 46.9 45.3 50.4 9 47.8 46.2 51.1 10 48.647.1 52.1

Table III is a comparison of the relative amounts and combinations ofdrug and resin complexes of the present invention. Table III is only anexemplar table and the skilled artisan will recognize the numerouscombinations of drug and resin complexes. Aspirin/ mgs DrugPropoxyPhene/ Naproxen/ DextroMethorphan/ PseudoePhedrine/ Resin Codeineacetaminophen Gauifenesin Carbinoxamine Phenylephrine IRP-69 50-100050-1000 50-1000 50-1000 50-1000 80-2000 IR-20 50-1000 50-1000 50-100050-1000 50-1000 80-2000 IRC-50 50-1000 50-1000 50-1000 50-1000 50-100080-2000 IRP-58 50-1000 50-1000 50-1000 50-1000 50-1000 80-2000 IRP-6450-1000 50-1000 50-1000 50-1000 50-1000 80-2000 IRP-69 50-1000 50-100050-1000 50-1000 50-1000 80-2000 XE-69 50-1000 50-1000 50-1000 50-100050-1000 80-2000 IR-120 50-1000 50-1000 50-1000 50-1000 50-1000 80-2000XYS-40013.00 50-1000 50-1000 50-1000 50-1000 50-1000 80-2000XYS-40010.00 50-1000 50-1000 50-1000 50-1000 50-1000 80-2000

In addition to pharmaceutically active drugs used in conjunction withavailable resins, the inventors have contemplated the use of other knownactive compounds with the present invention, e.g., herbicides,fungicides, insecticides, acaricides, nematicides, bird repellants,plant nutrients and agents that improve soil structure.

In addition, the present invention provides a method to enhance theefficiency of preparing ion exchange resins and pharmaceutically activedrug-resin compound preparations. Unlike the present invention, theprior art describes forming complexes between ion exchange resins andvarious compounds by dissolving the compound of interest in a media andsuspending the ion exchange resin in that preparation. After a period,the dissolved compound binds to the ion exchange resin to form acompound/resin complex. The media and any remaining unbound compound areseparated from the compound/resin complex by filtering or othermechanical methods. The compound/resin complex is then washed to removefree compound and dried. The compound/resin complex can then be treatedas necessary to swell the complex and coated with a rate-controllingmembrane to control the rate of release of the compound from the resinwhen exposed to regenerating media.

The present inventors recognized that in the procedures currently usedin the art to prepare pharmaceutical compositions, there are numeroussteps in the loading procedures (e.g., loading procedure, dry process,treatment procedure and/or the final drying process) that limit theefficiency of the pharmaceutical composition due to pharmaceuticallyactive drug loss, e.g., some portion of the pharmaceutically activedrugs of interest may be removed during filtering and/or washing of thepharmaceutical composition. Generally, the pharmaceutically active drugsloss is 10% -25% given the procedures currently used in the art (e.g.,the compound loss is 16%, see example 1 in the '778 patent).

The present invention provides a near quantitative utilization of thepharmaceutically active drugs of interest while minimizing thepurification process, e.g., washing and transferring thepharmaceutically active drugs and pharmaceutical compositions. Thepresent invention does not require the total disolvation of thepharmaceutically active drugs, allows the use of less pure reagents andrequires a shorter loading time. The present invention includes awash-free process that provides a near quantitative utilization of thepharmaceutically active drugs of interest. In addition, treated postloading, the particle size of the pharmaceutically active drugs/resincomplex is reduced with little or no agglomeration of the resinparticles during preparation. Table IV illustrates the improved drugutilization by reduced losses of the pharmaceutical composition. Whenthe present invention is compared to the procedure described in the '778patent, it is clear that less pharmaceutically active drugs are lostwith the present invention. TABLE IV ‘778 Patent Present InventionActive Drug Lost 10%-25%   <2% Phenylpropanolamine Lost   16% —Hydrocodone bitartrate Lost >22% <1.0% Phenylephrine HCl Lost —   1.7%

When the pharmaceutically active drugs/resin complex is exposed to asolution (e.g., aqueous media) the unbound pharmaceutically active drugs(i.e., free compound) may dissolve and migrate into the wetted ionexchange resin or migrate out of the wetted ion exchange resin dependingon the equilibrium established. The final distribution or concentrationof the unbound pharmaceutically active drugs and the boundpharmaceutically active drugs are controlled by an equilibrium reactionsubject to variables, well known to the skilled artisan, e.g., compoundto resin affinity, compound to resin ratio, media used, presence ofcompeting species or absence of competing species. In addition, therate-controlling membrane adjusts the rate at which a new equilibrium isachieved by controlling the interaction with the solvent; however, itdoes not change the ultimate equilibrium distribution.

For example, the present invention provides a pharmaceutical compositionhaving a pharmacologically active drug absorbed onto an ion exchangeresin particles (e.g., IRP-69) to form a pharmaceutically activedrugs-resin complex particle. The pharmacologically active drug (orother compound) and ion exchange resin are suspended/dissolved in asuitable ratio in water and the pharmaceutically active drugs areallowed to load onto the ion exchange resin particles. Optionally, aswelling agent may be added to the suspension at this time. After asuitable period of time (e.g., several hours) the suspension is filteredand the filter cake (e.g., the fraction containing damp resin complexplus some portion of unbound compound) and liquid filtrate (e.g., thefraction containing the remaining portion of the compound and perhapsswelling agent) recovered separately. The suitable period of time mayrange from 0.1 hours to 24 hours and may be of any increment to provideacceptable loading, e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9,1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0,14.0, 15.0, 16.0, 17.0, 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0 or acombination thereof The filter cake is then dried and the filtrate isthen applied back onto the dried filter cake using fluid bed coatingequipment or other suitable apparatus or process known to the skilledartisan. After application of the filtrate, the prepared complexcontains virtually all the compound and all the treating agents presentin the original suspension.

The prepared compound/resin complex may then be coated with arate-controlling membrane to achieve a chosen release profile. Althougha portion of the compound is not ionically bound to the ion exchangeresin at time of preparation, when wetted, (in dissolution media, insyrup or by ingestion) the free drug is available to dissolve and may bereleased or continue to load onto the ion exchange resin depending uponmedia used and formulation ratios.

The '778 patent, and other procedures in which free pharmaceuticallyactive drugs are removed, allows a portion of the bound pharmaceuticallyactive drug to equilibrate quickly into the dissolution media uponhydration. This equilibration allows a modest burst effect that isattenuated by the coating. In the present invention, a portion of theunbound drug equilibrates into the dissolution media, exhibiting asimilar profile that is modulated by the coating. The extent of thisburst effect may be controlled by manipulation of formulationparameters. For example, the present invention provides a modifiedrelease profile as illustrated in Table V below. Table V provides thedata for the release profile for Phenylephrine Hydrochloride from thedrug-resin complex with a 25% coating and FIG. 1 is a graph of therelease profile of Phenylephrine Hydrochloride from the drug-resincomplex with a 25% coating. TABLE V Time % Released 0.5 hr 25.5% 1.0 hr30.5% 3.0 hr 61.0% 6.0 hr 93.0% 12.0 hr  97.0%

Table VI provides the data for the release profile for hydrocodone/resinprepared by the present invention and FIG. 2 is a graph of the releaseprofile for a hydrocodone-resin complex prepared by the presentinvention. TABLE VI Time Sample A 0.5 Hr 38.6% 1.0 Hr 44.4% 3.0 Hr 66.0%6.0 Hr 80.4%

In addition, the present invention provides a method of making adrug-resin compound by loading in a solution one or more drugs onto oneor more ion exchange resin particles to form a drug-loaded resinparticle. The drug-loaded resin particle is separated from the solutionand dried. The solution is recombined with the drug-loaded resin to addmore drugs onto the drug-loaded resin particle. The drug-loaded resinparticle is dried after recombining the drug-loaded resin particle withthe solution.

The separating may be accomplished by filtration, extraction,distillation, precipitation, amalgamation or a combination or seriesthereof. The separation may involve one or a series of separationprocedures and may be similar or different in type or in reagents orcomponents used. Solvents may include the solvents known to the skilledartisan, e.g., a non-limiting example includes hexane, benzene, toluene,diethyl ether, chloroform, ethyl acetate, dichloromethane, 1,4-dioxane,tetrahydrofuran, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, acetic acid, n-butanol, isopropanol, n-propanol, ethanol,methanol, formic acid, water, and mixtures or combinations thereof. thesolvent may also be in-part or a mixture of alkanes (C5-C8), benzene,benzenethiol, carbon tetrachloride, chlorobenzene, chloroform,cyclohexanethiol, 2-diethylaminoethanol, ethylene dichloride(1,2-dichloroethane), ethyl ether, ethylene glycol monobutyl ether,ethylene glycol monobutyl acetate, ethylene glycol monoethyl ether,ethylene glycol monoethyl ether acetate, ethylene glycol monomethylether, ethylene glycol monomethyl ether acetate, glycidyl ethers,isopropyl alcohol, ketones, methyl alcohol, methylene chloride, phenol,propylene glycol ethers and their acetates, 1,1,2,2-tetrachloroethane,thiols, n-alkane mono, toluene, 1,1,1-trichloroethane,trichloroethylene, xylene, chloroethanes, chloroform, ethylenedibromide, ethylene dibromide, ethylene dichloride (1,2-dichloroethane)glycol ethers: 2-methoxyethanol, 2-ethoxyethanol, hexamethylphosphorictriamide, methylene chloride, halomethanes: methyl chloride, methylbromide, methyl iodide, 2-nitropropane, tetrachloroethylene(perchloroethylene), or trichloroethylene.

The loading step generally includes loading one or more drugs in asolution onto one or more ion exchange resin particles to form adrug-loaded resin particle. The solution may be formed in a variety ofmethods known to the skilled artisan, e.g., the one or more drugs may bein a solution; the one or more ion exchange resin particles may be insolution; both the one or more ion exchange resin particles and the oneor more drugs may be in a solution; neither the one or more ion exchangeresin particles, nor the one or more ion exchange resin particles may bein a solution; the one or more ion exchange resin particles may be in asolution and combined with another reagent or solution. The step ofloading may last from between about 0.1 and about 12 hours or longerthan about 12 hours.

Furthermore, the one or more sugar alcohols may also be added to thedrug-loaded resin particle, e.g., mannitol, sorbitol, xylitol, maltitol,lactitol, 1,3-dihydroxypropane, inositol glucose, sucrose and mixturesor combinations thereof.

A second drug may be added to the loaded resin particle selected fromnarcotic analgesics, sympathomimetics, antitussives, analgesicsantiemetics, anticholinergics, muscle relaxants, bronchodilators,antibiotics, antidepressants, antiasthmatics, antineoplastics,antiepileptics, cardiovascular agents, mixtures and combinationsthereof.

Examples of the insecticide, acaricide and nematocide that may be usedwith the present invention include pyrethroid compounds (e.g.,permethrin, cypermethrin, fenvarelate, esfenvarelate, fenpropathrin,biphenthrin, deltamethrin, fluvalinate, flucythrinate, allethrin,d-allethrin, prallethrin, cyphenothrin, phenothrin, resmethrin,tefluthrin, empenthrin, acrinathrin, cyhalothrin, cyfluthrin,etofenprox, halfenprox, silafluofen, tralomethrin, cycloprothrin,esbiothrin, transfluthrin, terallethrin, imiprothrin and1-ethynyl-2-fluoro-2-pentenyl3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate);organophosphorus compounds (e.g., cyanophos, fenthion, fenitrothion,parathion, methylparathion, pirimiphos-methyl, diazinon, isoxathion,pyridaphenthion, chlorpyrifos, chlorpyrifos-methyl, oxydeprofos,vamidothion, malathion, phenthoate, dimethoate, thiometon, disulfoton,phosalone, phosmet, methidathion, prothiofos, sulprofos, profenofos,azinphosmethyl, pyraclofos, salithion, tetrachlorvinphos, dichlorvos,monocrotophos, naled, dimethylvinphos, propaphos, acephate, metamidofosand ethion; carbamate compounds such as carbaryl, metolcarb, isoprocarb,fenobcarb, propoxur, XMC, ethiofencarb, bendiocarb, pyrimicarb,carbosulfan, carbofuran, benfuracarb, furathiocarb, methomyl,thiodicarb, oxamyl, alanycarb, metoxadiazone and fenothiocarb);neonicotinoids (e.g., nitroiminoimidazolidine derivatives,nitrovinylidenediamine derivatives [e.g.N-[(6-chloro-3-pyridylmethyl)-N-ethyl-N′-methyl-2-nitrovinylidenediamine(common name: nitenpyram)], nitroguanidine derivatives, cyanoacetamidinederivatives, N1-[(6-chloro-3-pyridyl)methyl]-N2-cyano-N1-methylacetamidine, cyanoiminothiazolidine derivatives,1-(2-chloro-5-pyridylmethyl)-2-cyanoiminothiazolidine,nitroiminotetrahydro-1,3,5-oxadiazine derivatives,3-[(2-chloro-5-thiazolyl)methyl]-5-methyl-4-nitroiminotetrahydro-1,3,5-oxadiazine(common name: thiamethoxam), nitroiminohexahydro-1,3,5-triazinederivatives,3,5-dimethyl-1-[(2-chloro-5-thiazolyl)methyl]-2-nitroiminohexahydro-1,3,5-triazine;nereistoxin derivatives (e.g., cartap, bensultap and thiocyclam);chlorinated hydrocarbon compounds (e.g., benzoepin, dicofol andtetradifon; formamidine derivatives (e.g., amitraz and chlordimeform);phenylpyrazole derivatives (e.g., ethiprole); benzoylphenylureacompounds (e.g., diflubenzuron, teflubenzuron, chlorfluazuron,flufenoxuron, triflumuron, hexaflumuron, lufenuron and novaluron);triazine derivatives (e.g., cyromazine); thiadiazine derivatives (e.g.,buprofezine); juvenoid compounds (e.g., methoprene, hydroprene,fenoxycarb and diofenolan); tebufenozide; methoxyfenozide; halofenozide;chromafenozide; chlorofenapir; phenisobromolate; quinomethionate;propargit; fenbutatin oxide; hexythiazox; etoxazole; clofentezine;fenpyroximate; tebufenpyrad; pyrimidifen; polynactin complex;milbemectin; avermectin; ivermectin and azadirachtin.

Specific examples of a insecticides include:2,3,5,6-tetrafluorobenzyl-chrysanthemate;2,3,5,6-tetrafluorobenzyl-2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate; 4-methyl-2,3,5,6-tetrafluorobenzyl-chrysanthemate;4-methyl-2,3,5,6-tetrafluorobenzyl-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate;4-methyl-2,3,5,6-tetrafluorobenzyl-2,2-dimethyl-3-(2,2-difluorovinyl)cyclopropanecarboxylate; 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-chrysanthemate;4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-2,2-dimethyl-3-(1-propenyl)cyclopropanecarboxylate;2,3,4,5,6-pentafluorobenzyl-2,2-dimethyl-3-(2-chloro-2-trifluoromethylvinyl)cyclopropanecarboxylate; and4-propargyl-2,3,5,6-tetrafluorobenzyl-3-(1-propenyl)-2,2-dimethylcyclopropanecarboxylate. Further, as examples of compounds other than thoseexpressed by formula (I), the following chemicals may be given:4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-2,2,3,3-tetramethylcyclopropanecarboxylate; and4-propargyl-2,3,5,6-tetrafluorobenzyl-2,2,3,3-tetramethylcyclopropanecarboxylate.

Suitable herbicides include: anilides (e.g., diflufenican and propanil),arylcarboxylic acids (e.g., dichloropicolinic acid, dicamba andpicloram), aryloxyalkanoic acids (e.g., 2,4-D, 2,4-DB, 2,4-DP,fluroxypyr, MCPA, MCPP and triclopyr), aryloxy-phenoxy-alkanoic esters(e.g., diclofop-methyl, fenoxaprop-ethyl, fluazifop-butyl,haloxyfop-methyl and quizalofop-ethyl), azinones (e.g., chloridazon andnorflurazon), carbamates (e.g., chlorpropham, desmedipham, phenmediphamand propham), chloroacetanilides (e.g., alachlor, acetochlor, butachlor,metazachlor, metolachlor, pretilachlor and propachlor), dinitroanilines(e.g., oryzalin, pendimethalin and trifluralin), diphenyl ethers (e.g.,acifluorfen, bifenox, fluoroglycofen, fomesafen, halosafen, lactofen andoxyfluorfen), ureas (e.g., chlortoluron, diuron, fluometuron,isoproturon, linuron and methabenzthiazuron), hydroxylamines (e.g.,alloxydim, clethodim, cycloxydim, sethoxydim and tralkoxydim),imidazolinones (e.g., imazethapyr, imazamethabenz, imazapyr andimazaquin), nitriles (e.g., bromoxynil, dichlobenil and ioxynil),oxyacetamides (e.g., mefenacet), sulphonylureas (e.g., amidosulfuron,bensulfuron-methyl, chlorimuron-ethyl, chlorsulfuron, cinosulfuron,metsulfuron-methyl, nicosulfuron, primisulfuron, pyrazosulfuron-ethyl,thifensulfuron-methyl, triasulfuron and tribenuron-methyl),thiocarbamates (e.g., butylate, cycloate, di-allate, EPTC, esprocarb,molinate, prosulfocarb, thiobencarb and tri-allate), triazines (e.g.,atrazine, cyanazine, simazine, simetryne, terbutryne and terbutylazine),triazinones (e.g., hexazinone, metamitron and metribuzin), others (e.g.,aminotriazole, benfuresate, bentazone, cinmethylin, clomazone,clopyralid, difenzoquat, dithiopyr, ethofumesate, fluorochloridone,glufosinate, glyphosate, isoxaben, pyridate, quinchlorac, quinmerac,sulphosate and tridiphane).

The present invention provides a method and composition for thecontrolled-release of one or more pharmaceutical compositions throughthe loading directly of a pharmaceutically active composition orpro-active pharmaceutical composition onto an ion exchange resin andthen applying a coating to form a coated drug-resin complex. In someinstances, the ion exchange resin may be pre-swollen by treatment withother agents, e.g., sorbitol.

For example, to prepare the coated pharmaceutical composition-resincomplex, the pharmaceutical composition is dissolved in a suitablesolvent or suspended in a suitable vehicle. The solvent containing thepharmaceutical composition is applied directly to the resin. Noadditional effort is made to reach equilibrium or to cause the compoundto bind onto the ion exchange resin. One common method of loading thepharmaceutical composition to the ion exchange resin is to dissolve thepharmaceutical composition in water and spray it onto the ion exchangeresin in fluid-bed coating apparatus; however, any other method ofloading may be used. The loaded pharmaceutical composition-resin complexmay then be coated using any suitable membrane material (e.g.,ethylcellulose or any other common coating material may be used) tocontrol the flow rate.

Upon placing the loaded, coated pharmaceutical composition-resin into anaqueous media (e.g., water bases, syrup base or gastric media), thecomplex quickly hydrates. When hydrated, a portion of the compound ofinterest will dissolve, and in the absence of competing ionic species,will equilibrate with the ion exchange resin and water.

Thermodynamically, this equilibrium is independent of the type orthickness (or even the presence) of the coating, and dependent upon themedia used, the properties of the pharmaceutical composition itself andthe proportions of pharmaceutical composition, the ion exchange sites ofthe ion exchange resin and any competing species. Thus when placed intoan aqueous, non-ionic media (e.g., water or syrup base) thepharmaceutical composition will equilibrate with a substantial portionof the pharmaceutical composition bound to the ion resin and anotherportion free in the media. When competing ions are introduced, thepharmaceutical composition is displaced from the ion exchange resin.

The present invention eliminates the need to pre-equilibrate apharmaceutical composition with the ion exchange resin, the need toseparate the pharmaceutical composition-resin complex from excesscompound, the need to dry the isolated pharmaceutical composition-resincomplex and the need to pre-treat the pharmaceutical composition-resincomplex after loading. In addition the present invention provides amethod of reducing or eliminating the loss of active pharmaceuticalcomposition to filtering and washing.

EXAMPLE VII

The ion exchange resin IRP-69 is pretreated by physically mixing 70%sorbitol solution with dry IRP-69. The dry ion exchange resin was placedinto a planetary mixer and a sorbitol solution was poured into the ionexchange resin while mixing until the liquid was taken up by the ionexchange resin and appearance was visually uniform. During this process,the volume of the ion exchange resin increased appreciably.

A solution of phenylephrine HCl in water was prepared and applied to thepre-treated ion exchange resin using a fluid-bed coating unit. However,other apparatus such as planetary mixer or ribbon blender equipped toremove excess solvent may also be used. The drug-resin complex was thencoated using ethylcellulose. The resulting product displayed stable,low-level release in non-ionic media (e.g., Purified Water USP) and asustained-release profile in conventional dissolution media. The releaseprofile can be manipulated using all the same tools (e.g., loadingratio, polymer selection, coating thickness, drug or resin selection) asin prior art. Equilibrium distribution in non-ionic media:

-   -   16% of phenylephrine HCl in solution    -   84% of phenylephrine retained by ion exchange resin

Release profile of phenylephrine HCl which simulates gastric media (1hour) followed by simulated intestinal fluid. Time Percentage Released0.5 hour 48% 1.0 hour 55% 1.5 hour 76% 2.0 hour 81% 4.0 hour 92%

The present invention also provides compositions and methods ofreleasing two or more pharmaceutical compositions. For example, aphenylephrine HCl and IRP-69 drug-resin complex is prepared using any ofthe methods disclosed herein or as disclosed in the prior art. Thephenylephrine HCl and IRP-69 drug-resin complex is directly loaded witha second drug (e.g., compound B) by spray applying a solution containingcompound B to the phenylephrine HCl-IRP-69 drug-resin complex. Thislayer loaded complex (compound B-phenylephrine HCl-IRP-69 drug-resincomplex) is then coated as previously described. A sustained-releaseprofile of both phenylephrine HCl and Compound B was achieved, as seenin Table VII. TABLE VII Time Phenylephrine HCl Released Compound BReleased 0.5 hour 48% 34% 1.0 hour 55% 48% 1.5 hour 76% 75% 2.0 hour 81%87% 4.0 hour 92% 103%

The present invention provides a sustained-release coated pharmaceuticaldrug-ion exchange resin composition. The composition includes a coatingapplied to a pharmaceutically active drug applied directly to anon-equilibrated ion exchange resin to form a coated drug-resin complex.The coated drug-resin complex is shelf stable.

The coated drug-resin complex may also include the addition of one ormore sugar alcohols to the non-equilibrated ion exchange resin (e.g.,mannitol, sorbitol, xylitol, maltitol, lactitol, 1,3-dihydroxypropane,inositol glucose, sucrose or combinations and mixtures thereof) in therange of between about 0.01% and about 10% sorbitol by weight. Thecoated drug-resin complex may be in part a solution, a suspension, acream, an ointment, a lotion, a capsule, a caplet, a softgel, a gelcap,a tablet, a suppository, an enema, an elixir, a syrup, an emulsion, afilm, a granule, a gum, an insert, a jelly, a foam, a paste, a pastille,a pellet, a spray, a troche, a lozenge, a disk, a magma, a poultice, awafer or combinations thereof.

The non-equilibrated ion exchange resin includes dipropylene glycoldiallyl ether, polyglycol diallyl ether, triethylene glycol divinylether, hydroquinone diallyl ether, tetraallyloxyethanoyl, vinyl ether,vinyl acetate, vinyl butylbenzoate, crotonic acid, polyfunctionalalcohol, tetraethylene glycol diacrylate, triallylamine,trimethylolpropane diallyl ether, methylenebisacrylamide,divinylbenzene, phthalic, sulphonphthalic acid, ethylene glycol,polymethyl siloxane α, γ-hydroxypropyl or combinations thereof.

The pharmaceutically active drug includes compounds selected from thefollowing catagories: narcotic analgesics, sympathomimetics,antitussives, analgesics antiemetics, anticholinergics, musclerelaxants, bronchodilators, antibiotics, antidepressants,antiasthmatics, antineoplastics, antiepileptics, cardiovascular agents,mixtures and combinations thereof. For example, codeine, dihydrocodeine,hydromorphone, morphine, pentazocine, propoxyphene, norephedrine,pseudoephedrine, dextromethorphan, aspirin, tramadol, metoclopramide,atropine, ipratropium bromide, scopolamine, cyclobenzaprine, papaverine,salbutamol, terbutaline and theophylline, amoxycillin, ampicillin,azlocillin, bacampicillin, cefamandole, cefonicid, cefotaxime,cefotetan, cefoxitin, ceftriaxone, mezlocillin, piperacillin, bupropion,nomifensine, nortriptyline, cromolyn, tamoxifen, valproic acid andphenvtoin, propranolol mixtures and combinations thereof.

The present invention provides a method of forming a sustained-releasecoated pharmaceutical drug-ion exchange resin composition by applying apharmaceutically active drug directly to a non-equilibrated ion exchangeresin to form a drug-resin complex and applying a coating to thedrug-resin complex wherein the drug-resin complex is shelf stable inconventional dissolution media. The method may also include contactingthe non-equilibrated ion exchange resin with between about 0.01% and 10%by weight of one or more sugar alcohols, based on the combined weight ofthe sugar alcohol and the non-equilibrated ion exchange resin. Forexample, the one or more sugar alcohols comprise mannitol, sorbitol,xylitol, maltitol, lactitol, 1,3-dihydroxypropane, inositol glucose,sucrose, mixtures and combinations thereof.

In addition, the present invention provides a sustained-release coatedlayered pharmaceutical drug-ion exchange resin composition. The layeredpharmaceutical drug-ion exchange resin composition includes a firstpharmaceutically active drug applied directly to a non-equilibrated ionexchange resin to form a first drug-resin complex. One or more secondpharmaceutically active drugs are applied directly to the firstdrug-resin complex to form a layered-drug-resin complex. A coating isapplied to the layered-drug-resin complex wherein the layered-drug-resincomplex is shelf stable in conventional dissolution media. The number oflayers will be dependent on the desired release profiles and the numberof pharmaceutically active drugs to be used. The first pharmaceuticallyactive drug and each of the one or more second pharmaceutically activedrugs may independently include codeine, dihydrocodeine, hydromorphone,morphine, pentazocine, propoxyphene, norephedrine, pseudoephedrine,dextromethorphan, aspirin, tramadol, metoclopramide, atropine,ipratropium bromide, scopolamine, cyclobenzaprine, papaverine,salbutamol, terbutaline and theophylline, amoxycillin, ampicillin,azlocillin, bacampicillin, cefamandole, cefonicid, cefotaxime,cefotetan, cefoxitin, ceftriaxone, mezlocillin, piperacillin, bupropion,nomifensine, nortriptyline, cromolyn, tamoxifen, valproic acid andphenvtoin, propranolol mixtures and combinations thereof.

For example, the first pharmaceutically active drug is applied to thelayered pharmaceutical drug-ion exchange resin to form a firstdrug-resin complex. A second pharmaceutically active drug is thenapplied directly to the first drug-resin complex to form alayered-drug-resin complex. Optionally, a third, fourth, fifth, sixth,seventh or more pharmaceutically active drugs may be layered to create alayered composition that is shelf stable in conventional dissolutionmedia. Each layer may be similar or different in composition to create aspecific release profile. Each layer may independently be of similarcompounds, different compounds or mixtures of compounds providingnumerous combinations and release profiles. For example, the firstpharmaceutically active drug may be pseudoephedrine, the secondpharmaceutically active drug may be gauifenesin, the thirdpharmaceutically active drug may be pseudoephedrine, the fourthpharmaceutically active drug may be phenylephrine, and the fifthpharmaceutically active drug may be dextromethorphan to create alayered-drug-resin complex.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method, kit, reagent, orcomposition of the invention, and vice versa. Furthermore, compositionsof the invention can be used to achieve methods of the invention.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.” The use of the term “or” in the claims isused to mean “and/or” unless explicitly indicated to refer toalternatives only or the alternatives are mutually exclusive, althoughthe disclosure supports a definition that refers to only alternativesand “and/or.” Throughout this application, the term “about” is used toindicate that a value includes the inherent variation of error for thedevice, the method being employed to determine the value, or thevariation that exists among the study subjects.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps.

The term “or combinations thereof” as used herein refers to allpermutations and combinations of the listed items preceding the term.For example, “A, B, C, or combinations thereof” is intended to includeat least one of: A, B, C, AB, AC, BC, or ABC, and if order is importantin a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.Continuing with this example, expressly included are combinations thatcontain repeats of one or more item or term, such as BB, AAA, MB, BBC,AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan willunderstand that typically there is no limit on the number of items orterms in any combination, unless otherwise apparent from the context.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

1. A sustained-release coated pharmaceutical drug-ion exchange resincomposition comprising: a coating applied to a pharmaceutically activedrug applied directly to a non-equilibrated ion exchange resin to form acoated drug-resin complex, wherein the coated drug-resin complex isshelf stable.
 2. The composition of claim 1, further comprising theaddition of one or more sugar alcohols to the non-equilibrated ionexchange resin.
 3. The composition of claim 2, wherein the one or moresugar alcohols comprise mannitol, sorbitol, xylitol, maltitol, lactitol,1,3-dihydroxypropane, inositol glucose, sucrose or combinations andmixtures thereof.
 4. The composition of claim 3, wherein the one or moresugar alcohols comprises between about 0.01% and about 10% sorbitol byweight.
 5. The composition of claim 1, wherein the non-equilibrated ionexchange resin comprises a sulfonic acid cation exchange resin.
 6. Thecomposition of claim 1, wherein the non-equilibrated ion exchange resincomprises dipropylene glycol diallyl ether, polyglycol diallyl ether,triethylene glycol divinyl ether, hydroquinone diallyl ether,tetraallyloxyethanoyl, vinyl ether, vinyl acetate, vinyl butylbenzoate,crotonic acid, polyfunctional alcohol, tetraethylene glycol diacrylate,triallylamine, trimethylolpropane diallyl ether, methylenebisacrylamide,divinylbenzene, phthalic, sulphonphthalic acid, ethylene glycol,polymethyl siloxane α, γ-hydroxypropyl or combinations thereof.
 7. Thecomposition of claim 1, wherein the pharmaceutically active drugcomprises narcotic analgesics, sympathomimetics, antitussives,analgesics antiemetics, anticholinergics, muscle relaxants,bronchodilators, antibiotics, antidepressants, antiasthmatics,antineoplastics, antiepileptics, cardiovascular agents, mixtures andcombinations thereof.
 8. The composition of claim 1, wherein thepharmaceutically active drug comprises codeine, dihydrocodeine,hydromorphone, morphine, pentazocine, propoxyphene, norephedrine,pseudoephedrine, phenylephrine, gauifenesin dextromethorphan, aspirin,tramadol, metoclopramide, atropine, ipratropium bromide, scopolamine,cyclobenzaprine, papaverine, salbutamol, terbutaline and theophylline,amoxycillin, ampicillin, azlocillin, bacampicillin, cefamandole,cefonicid, cefotaxime, cefotetan, cefoxitin, ceftriaxone, mezlocillin,piperacillin, bupropion, nomifensine, nortriptyline, cromolyn,tamoxifen, valproic acid and phenvtoin, propranolol mixtures andcombinations thereof.
 9. The composition of claim 1, wherein the coateddrug-resin complex comprises a solution, a suspension, a cream, anointment, a lotion, a capsule, a caplet, a softgel, a gelcap, a tablet,a suppository, an enema, an elixir, a syrup, an emulsion, a film, agranule, a gum, an insert, a jelly, a foam, a paste, a pastille, apellet, a spray, a troche, a lozenge, a disk, a magma, a poultice, awafer or combinations thereof.
 10. A method of forming asustained-release coated pharmaceutical drug-ion exchange resincomposition comprising the step of: applying a pharmaceutically activedrug directly to a non-equilibrated ion exchange resin to form adrug-resin complex; and applying a coating to the drug-resin complex,wherein the drug-resin complex is shelf stable.
 11. The method of claim10, further comprising contacting the non-equilibrated ion exchangeresin with between about 0.01% and 10% by weight of one or more sugaralcohols, based on the combined weight of the sugar alcohol and thenon-equilibrated ion exchange resin.
 12. The method of claim 11, whereinthe one or more sugar alcohols comprise an aqueous solution.
 13. Themethod of claim 12, wherein the one or more sugar alcohols comprisemannitol, sorbitol, xylitol, maltitol, lactitol, 1,3-dihydroxypropane,inositol glucose, sucrose, mixtures and combinations thereof.
 14. Themethod of claim 10, wherein the non-equilibrated ion exchange resincomprises a sulfonic acid cationic exchange resin particles.
 15. Themethod of claim 10, wherein the non-equilibrated ion exchange resincomprises dipropylene glycol diallyl ether, polyglycol diallyl ether,triethylene glycol divinyl ether, hydroquinone diallyl ether,tetraallyloxyethanoyl, vinyl ether, vinyl acetate, vinyl butylbenzoate,crotonic acid, polyfunctional alcohol, tetraethylene glycol diacrylate,triallylamine, trimethylolpropane diallyl ether, methylenebisacrylamide,divinylbenzene, phthalic, sulphonphthalic acid, ethylene glycol,polymethyl siloxane α, γ-hydroxypropyl or combination thereof.
 16. Themethod of claim 10, wherein the pharmaceutically active drug comprisesnarcotic analgesics, sympathomimetics, antitussives, analgesicsantiemetics, anticholinergics, muscle relaxants, bronchodilators,antibiotics, antidepressants, antiasthmatics, antineoplastics,antiepileptics, cardiovascular agents, mixtures and combinationsthereof.
 17. The composition of claim 10, wherein the pharmaceuticallyactive drug comprises codeine, dihydrocodeine, hydromorphone, morphine,pentazocine, propoxyphene, norephedrine, pseudoephedrine,dextromethorphan, phenylephrine, gauifenesin, aspirin, tramadol,metoclopramide, atropine, ipratropium bromide, scopolamine,cyclobenzaprine, papaverine, salbutamol, terbutaline and theophylline,amoxycillin, ampicillin, azlocillin, bacampicillin, cefamandole,cefonicid, cefotaxime, cefotetan, cefoxitin, ceftriaxone, mezlocillin,piperacillin, bupropion, nomifensine, nortriptyline, cromolyn,tamoxifen, valproic acid and phenvtoin, propranolol mixtures andcombinations thereof.
 18. A pharmaceutical composition made according tothe method of claim
 10. 19. A sustained-release coated layeredpharmaceutical drug-ion exchange resin composition comprising: a firstpharmaceutically active drug applied directly to a non-equilibrated ionexchange resin to form a first drug-resin complex; one or more secondpharmaceutically active drugs applied directly to the first drug-resincomplex to form a layered-drug-resin complex; and a coating applied tothe layered-drug-resin complex, wherein the layered-drug-resin complexis shelf stable.
 20. The composition of claim 19, wherein the ionexchange resin comprises dipropylene glycol diallyl ether, polyglycoldiallyl ether, triethylene glycol divinyl ether, hydroquinone diallylether, tetraallyloxyethanoyl, vinyl ether, vinyl acetate, vinylbutylbenzoate, crotonic acid, polyfunctional alcohol, tetraethyleneglycol diacrylate, triallylamine, trimethylolpropane diallyl ether,methylenebisacrylamide, divinylbenzene, phthalic, sulphonphthalic acid,ethylene glycol, polymethyl siloxane α, γ-hydroxypropyl or combinationsthereof.
 21. The composition of claim 19, wherein the firstpharmaceutically active drug and each of the one or more secondpharmaceutically active drugs independently comprise codeine,dihydrocodeine, hydromorphone, morphine, pentazocine, propoxyphene,norephedrine, pseudoephedrine, phenylephrine, gauifenesin,dextromethorphan, aspirin, tramadol, metoclopramide, atropine,ipratropium bromide, scopolamine, cyclobenzaprine, papaverine,salbutamol, terbutaline and theophylline, amoxycillin, ampicillin,azlocillin, bacampicillin, cefamandole, cefonicid, cefotaxime,cefotetan, cefoxitin, ceftriaxone, mezlocillin, piperacillin, bupropion,nomifensine, nortriptyline, cromolyn, tamoxifen, valproic acid andphenvtoin, propranolol mixtures and combinations thereof.